WO2020239658A1 - Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies - Google Patents

Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies Download PDF

Info

Publication number
WO2020239658A1
WO2020239658A1 PCT/EP2020/064368 EP2020064368W WO2020239658A1 WO 2020239658 A1 WO2020239658 A1 WO 2020239658A1 EP 2020064368 W EP2020064368 W EP 2020064368W WO 2020239658 A1 WO2020239658 A1 WO 2020239658A1
Authority
WO
WIPO (PCT)
Prior art keywords
independently selected
diseases
compound
particular embodiment
alkyl
Prior art date
Application number
PCT/EP2020/064368
Other languages
English (en)
Inventor
Luke Jonathan ALVEY
Denis BUCHER
Nicolas Desroy
Hélène Marie JARY
Christophe Peixoto
Taoues TEMAL-LAÏB
Amynata TIRERA
Florence Marie-Emilie Bonnaterre
Béranger DUTHION
Original Assignee
Galapagos Nv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to KR1020217042863A priority Critical patent/KR20220015450A/ko
Priority to EP20728465.4A priority patent/EP3976189A1/fr
Application filed by Galapagos Nv filed Critical Galapagos Nv
Priority to JP2021570425A priority patent/JP2022534578A/ja
Priority to CR20210586A priority patent/CR20210586A/es
Priority to CA3141683A priority patent/CA3141683A1/fr
Priority to CN202080039185.0A priority patent/CN113924146A/zh
Priority to BR112021023900A priority patent/BR112021023900A2/pt
Priority to SG11202112652RA priority patent/SG11202112652RA/en
Priority to EA202193281A priority patent/EA202193281A1/ru
Priority to AU2020281650A priority patent/AU2020281650A1/en
Priority to MX2021013803A priority patent/MX2021013803A/es
Priority to PE2021001955A priority patent/PE20220503A1/es
Priority to US17/614,854 priority patent/US20220340548A1/en
Publication of WO2020239658A1 publication Critical patent/WO2020239658A1/fr
Priority to IL288375A priority patent/IL288375A/en
Priority to CONC2021/0017656A priority patent/CO2021017656A2/es

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to compounds, methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, uses and methods for the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases by administering the compounds of the invention.
  • the compounds of the invention may inhibit Salt-Inducible Kinases (“SIK” kinases). BACKGROUND OF THE INVENTION
  • Protein kinases belong to a large family of structurally related enzymes which are responsible for the control of a wide variety of cellular signal transduction processes. In particular, they have been shown to be key regulators in cellular functions including for example proliferation, metabolism, and apoptosis. Consequently, defective control of protein phosphorylation which leads to uncontrolled signaling is involved in a number of diseases, including for example, inflammation, allergies, cancer, autoimmune diseases, CNS disorders, and angiogenesis.
  • IL-10 interleukin-10
  • Adenosine Monophosphate-activated Protein Kinases belong to the protein kinase family, which comprises Salt-Inducible Kinases (SIKs), a family of serine/threonine kinases widely expressed in the body, and involved in particular in cellular energy homeostasis.
  • SIKs Salt-Inducible Kinases
  • SIK3 Three SIK isoforms have been identified, named SIK1 (also referred as SNFI-Like Kinase (SNF1LK) or Myocardial Snfl-Iike Kinase (MSK)), SIK2 (SNF1LK2 or KIAA0781) and SIK3 (KIAA0999) (Katoh et al.2004).
  • the SIKs play a number of roles in different cell types. They have been found to phosphorylate a number of substrates including CREB-responsive transcriptional co-activator (CRTC) proteins and Histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes.
  • CRTC CREB-responsive transcriptional co-activator
  • HDAC Histone de-acetylase
  • One of the roles of CRTC signalling relates to control the phenotype of macrophages, in particular polarisation of macrophages through phosphorylation of CRTC3 as measured by decreased proinflammatory cytokine IL-12 secretion and concomitant increased pro-resolution cytokine IL-10 secretion (Clark et al. 2012; Ozanne et al.2015).
  • SIK1 has recently been shown to be involved in skeletal muscle sensitivity in obese mice, and may be an interesting target to prevent type II diabetes (Nixon et al.2016), and diabetic nephropathy (Yu et al. 2013).
  • SIK2 and SIK3 have recently been identified to play a role in inflammation through the secretion of high levels of anti-inflammatory cytokines, in particular Interleukin-10 (IL-10) and very low levels of pro-inflammatory cytokines such as TNF ⁇ (Darling et al.2017).
  • IL-10 Interleukin-10
  • TNF ⁇ pro-inflammatory cytokines
  • SIK2 may be an interesting target for inflammatory diseases (Yao et al.2013).
  • SIK2 after oxygen-glucose deprivation enhances neuron survival (Sasaki et al.2011) or promotes melanogenesis in melanoma cells (Kumagai et al.2011).
  • therapeutic strategies are needed to modulate the stress cellular response, such as during ischaemia and post reperfusion of tissue, in the chronic phase of cardiac remodelling, in diabetes and neurodegenerative conditions, the rapid activation or degradation of the SIK proteins, following multiple kinds of stresses, makes them interesting targets in inflammatory, cardiac or metabolic diseases and neurodegenerative disorders.
  • SIK inhibition might also have application in cosmetology or pigmentation-related diseases to induce melanogenesis.
  • SIK proteins have also been involved in the regulation of the cell cycle.
  • Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers (Ashour Ahmed et al. 2010), moreover, expression of SIK3 was elevated in ovarian cancers, particularly in the serous subtype and at later stages (Charoenfuprasert et al.2011). Therefore SIK inhibition may be useful in the treatment of cancer.
  • the present invention is based on the identification of novel compounds, and their use in the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL- 12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • the compounds of the invention may be SIK inhibitors, and more particularly SIK1, SIK2 and/or SIK3 inhibitors.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases by administering the compounds of the invention.
  • inflammatory diseases autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL
  • W1 is N or CR3 and W2 is N or CH, with the proviso that W1 and W2 cannot both be N; one of X1, X2 and X3 is N and the other two are C;
  • Y is N or CR2b
  • N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R5 groups;
  • R1a is selected from
  • heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl, and
  • R1b and R1c are independently selected from
  • heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R9 groups, and
  • R1b and R1c together with the atom onto which they are attached form a C 3-6 cycloalkyl, or R 1b and R 1c together with the atom onto which they are attached form a 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R11 groups;
  • R2a and R2b are independently selected from
  • R3 is H, halo, or C 1-4 alkoxy optionally substituted with one or more independently selected -OH or C 1-4 alkoxy;
  • R4a is H or C 1-4 alkyl
  • R4b is selected from
  • heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R14b, and
  • heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;
  • R4c is H, C 3-7 cycloalkyl, or C1-6 alkyl optionally substituted with one or more independently selected halo or–CN;
  • each R5 is independently selected from:
  • - C 1-4 alkoxy optionally substituted with one or more independently selected halo or phenyl
  • - C 1-4 alkyl optionally substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy
  • - 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S;
  • each R6 is independently selected from
  • heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;
  • R7 is–OH, C 1-4 alkyl, C 1-4 alkoxy, -NR18aR18b, or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more–OH;
  • each R9 is independently halo, -OH, or C 1-4 alkyl optionally substituted with one or more–OH;
  • each R10a and R10b is independently H or C 1-4 alkyl optionally substituted with one or more -OH;
  • each R11 is independently selected from
  • each R12a and R12b is independently H or C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy; each R13 is independently selected from
  • heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;
  • each R14a and R14b is independently selected from
  • each R16 is independently selected from
  • each R17a and R17b is independently H or C 1-4 alkyl optionally substituted with one or more independently selected -OH or C 1-4 alkoxy;
  • R18a and R18b are independently H or C 1-4 alkyl optionally substituted with one or more independently selected -OH or C 1-4 alkoxy;
  • each R19a, R19b, R20a, R20b, R21a, and R21b is independently H or C 1-4 alkyl.
  • the compounds of the invention are provided for use in the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL- 23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • inflammatory diseases autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL- 23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases,
  • the compounds of the invention exhibit potency against SIK, particularly SIK1, SIK2 and/or SIK3, more particularly SIK3, which may result in a tolerogenic therapy (i.e. reduction of pro-inflammatory cytokines such as TNFa and IL-12, coupled with increased levels of anti-inflammatory cytokines such as IL-10 and TGF-b).
  • a tolerogenic therapy i.e. reduction of pro-inflammatory cytokines such as TNFa and IL-12, coupled with increased levels of anti-inflammatory cytokines such as IL-10 and TGF-b.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • the further therapeutically active ingredient is an agent for the treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • inflammatory diseases autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • the compounds of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.
  • the present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine.
  • the pharmaceutical composition is for use in the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
  • the articles‘a’ and‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.
  • an analogue means one analogue or more than one analogue.
  • Alkyl means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • alkyl groups are methyl (-CH 3 ), ethyl (-CH 2 -CH 3 ), n-propyl (-CH 2 -CH 2 -CH 3 ), isopropyl (-CH(CH 3 )2), n-butyl (- CH 2 -CH 2 -CH 2 -CH 3 ), tert-butyl (-C(CH 3 )3), sec-butyl (-CH(CH 3 )-CH 2 CH 3 ), isobutyl (-CH 2 -CH(CH 3 )2), n- pentyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), n-hexyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), and 1,2-dimethylbutyl (- CHCH 3 )-C(CH 3 )H2-CH 2 -CH 3 ).
  • Particular alkyl groups have between 1 and 4 carbon atoms
  • Alkylene refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight- chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 -CH 2 - ), or -CH(CH 3 )- and the like.
  • Alkynylene refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CoC-, -CH 2 - CoC-, and -C(CH 3 )H-CoCH-.
  • Alkoxy refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-C 1-6 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Amino refers to the radical -NH2.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified.
  • the term includes groups that include from 6 to 10 ring members.
  • Particular aryl groups include phenyl, and naphthyl.
  • Cycloalkyl refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified.
  • a cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Halo or‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • polycyclic refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two or three rings of atoms, most particularly two rings of atoms.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.
  • Heteroaryl means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the aromatic ring structure may have from 5 to 9 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.
  • Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
  • Heterocycloalkyl means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g.1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g.
  • heterocycloalkenyl means a‘heterocycloalkyl’, which comprises at least one double bond.
  • heterocycloalkenyl groups are shown in the following illustrative examples:
  • each W and Y is independently selected from -CH 2 -, -NH-, -O- and–S-.
  • each W and Y is independently selected from -CH 2 -, -NH-, -O- and–S-.
  • each W and Y is independently selected from -CH 2 -, -NH-, -O- and–S-.
  • each Y is selected from -CH 2 -, -NH-, -O- and–S-.
  • Haldroxyl refers to the radical -OH.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • Thiol refers to the group -SH.
  • term‘substituted with one or more’ refers to one to four substituents. In particular, it refers to one to three substituents. More particularly, it refers to one or two substituents. Most particularly, it refers to one substituent.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • “Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
  • salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • “Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, EtOH, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates.
  • solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • Subject includes humans. The terms‘human’,‘patient’ and‘subject’ are used interchangeably herein.
  • Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • The“effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Preventing refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • prophylaxis is related to‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • ‘Treating’ or‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • ‘treating’ or‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • ‘treating’ or‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treating” or“treatment” relates to slowing the progression of the disease.
  • inflammatory disease(s) refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints.
  • allergic airway disease e.g. asthma, rhinitis
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • endotoxin-driven disease states e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure
  • the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases
  • autoinflammatory diseases(s) refers to the group of diseases including Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease.
  • Cryopyrin-Associated Periodic Syndromes Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease.
  • CAPS Cryopyrin-Associated Periodic Syndromes
  • FMF Familial Mediterranean Fever
  • TRAPS Tumor necrosis factor receptor-associated periodic syndrome
  • Behçets Behçets
  • SJIA Systemic-Onset Juvenile Idiopathic Arth
  • autoimmune disease(s) refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g.
  • COPD chronic or inveterate asthma
  • bronchitis including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g.
  • autoimmune hepatitis primary sclerosing cholangitis, and primary biliary cirrhosis
  • Sjögren’s syndrome multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto’s and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • proliferative disease(s) refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis.
  • cancer e.g. uterine leiomyosarcoma or prostate cancer
  • myeloproliferative disorders e.g. polycythemia vera, essential thrombocytosis and myelofibrosis
  • leukemia e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia
  • multiple myeloma psoriasis
  • restenosis scleroderma or fibrosis
  • cancer refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel.
  • a cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain.
  • cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer,
  • cancer refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, reti
  • leukemia refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding.
  • leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
  • fibrotic disease(s) refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; tubulointerstitium fibrosis; glomerular
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • transplantation rejection refers to the acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.
  • the term‘diseases involving impairment of cartilage turnover’ includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
  • the term‘congenital cartilage malformation(s)’ includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.
  • the term‘diseases involving impairment of bone turnover’ includes conditions such as osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticosteroid induced osteoporosis and juvenile osteoporosis), osteoporosis caused through neoplastic bone marrow disorders, osteopenia, hormone deficiency (vitamin D deficiency, male and female hypogonadism), hormone excess (hyperprolactinaemia, excess glucocorticoid, hyperthyroidism , hyperparathyroidism), Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, hypophosphatasia.
  • osteoporosis including postmenopausal osteoporosis, male osteoporosis, glucocorticosteroid induced osteoporosis and juvenile osteoporosis
  • osteoporosis caused through neoplastic bone marrow disorders
  • osteopenia hormone deficiency (vitamin
  • the term‘disease(s) associated with hypersecretion of IL-6’ includes conditions such as Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and/or mesangial proliferative glomerulonephritis.
  • the term‘disease(s) associated with hypersecretion of of of TNF ⁇ , interferons, IL-12 and/or IL-23’ includes conditions such as systemic and cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • the term‘respiratory disease(s)’ refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves.
  • respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin- sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
  • asthma adult respiratory distress syndrome and allergic (extrinsic) asthma
  • non-allergic (intrinsic) asthma acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin- sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset
  • endocrine and/or metabolic disease(s) refers to the group of conditions involving the body’s over- or under-production of certain hormones, while metabolic disorders affect the body’s ability to process certain nutrients and vitamins.
  • Endocrine disorders include hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing’s syndrome and Addison’s disease), and ovarian dysfunction (including polycystic ovary syndrome), among others.
  • Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
  • a particular example of metabolic disorders is obesity and/or type II diabetes.
  • cardiovascular disease refers to diseases affecting the heart or blood vessels or both.
  • cardiovascular disease includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis (e.g., giant cell arteritis (GCA), retinal vasculitis, rheumatoid vasculitis), stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, cardiovascular disease refers to arrhythmia (atrial or ventricular or both); atherosclerosis
  • dermatological disorders include proliferative or inflammatory disorders of the skin such as atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term dermatological disorders refers to vitiligo.
  • abnormal angiogenesis associated disease(s) refers to diseases caused by the dysregulation of the processes mediating angiogenesis.
  • abnormal angiogenesis associated disease refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy.
  • Compound(s) of the invention are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits.
  • reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the C1-8 alkyl, C2-8 alkenyl, C6-10 optionally substituted aryl, and (C6-10 aryl)-(C 1-4 alkyl) esters of the compounds of the invention.
  • the present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the“natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an“unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • the term“unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form”).
  • the term“unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36Cl), chlorine-37 (37Cl), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11C, 18F, 150 and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a‘racemic mixture’.
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of p electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • the present invention is based on the identification of novel compounds, and their use in the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL- 12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • the compounds of the invention may be SIK inhibitors, more particularly SIK1, SIK2 and/or SIK3 inhibitors.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL- 23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases by administering the compounds of the invention.
  • inflammatory diseases autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-
  • W1 is N or CR3 and W2 is N or CH, with the proviso that W1 and W2 cannot both be N;
  • one of X1, X2 and X3 is N and the other two are C;
  • Y is N or CR2b
  • N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R5 groups;
  • R1a is selected from
  • heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl, and
  • R1b and R1c are independently selected from
  • heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R9 groups, and
  • R1b and R1c together with the atom onto which they are attached form a 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R11 groups;
  • R2a and R2b are independently selected from
  • R3 is H, halo, or C 1-4 alkoxy optionally substituted with one or more independently selected -OH or C 1-4 alkoxy;
  • R4a is H or C 1-4 alkyl
  • R4b is selected from
  • - C 1-6 alkyl optionally substituted with one or more independently selected R13
  • - C 3-7 cycloalkyl optionally substituted with one or more independently selected R14a
  • - 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R14b, and
  • heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;
  • R4c is H, C 3-7 cycloalkyl, or C1-6 alkyl optionally substituted with one or more independently selected halo or–CN;
  • each R5 is independently selected from
  • each R6 is independently selected from
  • heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;
  • R7 is–OH, C 1-4 alkyl, C 1-4 alkoxy, -NR18aR18b, or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more–OH;
  • each R11 is independently selected from
  • each R12a and R12b is independently H or C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy; each R13 is independently selected from
  • heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;
  • each R14a and R14b is independently selected from
  • each R16 is independently selected from
  • each R17a and R17b is independently H or C 1-4 alkyl optionally substituted with one or more independently selected -OH or C 1-4 alkoxy;
  • R18a and R18b are independently H or C 1-4 alkyl optionally substituted with one or more independently selected -OH or C 1-4 alkoxy;
  • each R19a, R19b, R20a, R20b, R21a, and R21b is independently H or C 1-4 alkyl.
  • the compound of the invention is according to Formula I, wherein W2 is N.
  • the compound of the invention is according to Formula I, wherein W2 is CH.
  • the compound of the invention is according to Formula I, wherein W1 is N.
  • the compound of the invention is according to Formula I, wherein W1 is CR3, and R3 is H.
  • the compound of the invention is according to Formula I, wherein W1 is CR3, and R3 is halo.
  • R3 is F, Cl, or Br.
  • R3 is F.
  • the compound of the invention is according to Formula I, wherein W1 is CR3, and R3 is C 1-4 alkoxy.
  • R3 is–O-CH 3 ,–O-CH 2 CH 3 , or -O-CH(CH 3 )2.
  • R3 is–O-CH 3 or–O-CH 2 CH 3 .
  • R3 is–O-CH 3 .
  • the compound of the invention is according to Formula I, wherein W 1 is CR3, and R3 is C 1-4 alkoxy substituted with one or more independently selected -OH or C 1-4 alkoxy.
  • R3 is–O-CH 2 CH 3 , or–O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected -OH or C 1-4 alkoxy.
  • R3 is C 1-4 alkoxy substituted with one, two, or three independently selected -OH or C 1-4 alkoxy.
  • R3 is C 1-4 alkoxy substituted with one or more independently selected–OH, -O-CH 3 ,–O-CH 2 CH 3 , or– O-CH(CH 3 ) 2 .
  • R3 is -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected -OH or C 1-4 alkoxy.
  • R3 is C 1-4 alkoxy substituted with one, two, or three independently selected -OH, -O-CH 3 ,– O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R3 is -O-CH 2 CH 3 , substituted with one, two, or three independently selected -OH or C 1-4 alkoxy. In a most particular embodiment, R3 is -O-CH 2 CH 2 -OH.
  • the compound of the invention is according to Formula I, wherein R2a is halo or–OH.
  • R2a is F, Cl, or–OH.
  • R2a is F.
  • the compound of the invention is according to Formula I, wherein R2a is C 1-4 alkyl.
  • R2a is -CH 3 ,–CH 2 CH 3 , or–CH(CH 3 ) 2 .
  • R2a is–CH 3 .
  • the compound of the invention is according to Formula I, wherein R2a is C 1-4 alkoxy.
  • R2a is–O-CH 3 ,–O-CH 2 CH 3 , or–O-CH(CH 3 )2.
  • R2a is–O-CH 3 or–O-CH 2 CH 3 .
  • R2a is–O-CH 3 .
  • the compound of the invention is according to Formula I, wherein R2a is C 1-4 alkoxy substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R2a is–O-CH 3 ,–O-CH 2 CH 3 , or–O-CH(CH 3 )2, each of which is substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R2a is C 1-4 alkoxy substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R2a is C 1-4 alkoxy substituted with one or more independently selected F, Cl, Br, -OH, -O-CH 3 , -O-CH 2 CH 3 , or –O-CH(CH 3 )2.
  • R2a is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 )2, each of which is substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R2a is C 1-4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, -OH, -O-CH 3 ,–O-CH 2 CH 3 , or -O-CH(CH 3 )2.
  • R2a is -O-CH 3 , substituted with one, two, or three independently selected halo.
  • R2a is -O-CH 2 CH 3 , substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R2a is -O-CHF2, -O-CH 2 CH 2 -OH, or -O-CH 2 CH 2 -O-CH 3 .
  • the compound of the invention is according to Formula I, wherein R2a is– NR12aR6b, and R12a and R12b are independently H or C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • R12a and R12b are both H.
  • one of R12a and R12b is H, and the other is C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • R12a and R12b are both C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • one of R12a and R12b is H, and the other is -CH 3 , -CH 2 CH 3 , or–CH(CH 3 ) 2 .
  • one of R12a and R12b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one–OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R2a is -NH-CH 3 , -NH-CH(CH 3 ) 2 , or -NH-CH 2 CH 2 -OH.
  • the compound of the invention is according to Formula I, wherein Z is–NR4c-, wherein the N atom and R2a together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one double bond, and R4c is as previously described.
  • Z is–NR4c-, wherein the N atom and R2a together with the atoms onto which they are attached form a fused 3-pyrroline or 1,2,3,6-tetrahydropyridine.
  • Z is –NR4c-, wherein the N atom and R2a together with the atoms onto which they are attached form a fused 1,2,3,6-tetrahydropyridine.
  • the compound of the invention is according to Formula IIa, IIb, IIc, IId, IIe, IIf, IIg, or IIh:
  • R1a, R1b, R1c, R4c, and Y are as described above.
  • the compound of the invention is according to any one of Formulae I-IIh, wherein R4c is H.
  • the compound of the invention is according to any one of Formulae I-IIh, wherein R4c is C 3-7 cycloalkyl.
  • R4c is cyclopropyl, cyclobutyl, or cyclopentyl.
  • R4c is cyclopropyl.
  • the compound of the invention is according to any one of Formulae I-IIh, wherein R4c is C 1-6 alkyl.
  • R4c is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 .
  • R4c is -CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIh, wherein R4c is C 1-6 alkyl substituted with one or more independently selected halo or–CN.
  • R4c is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one or more independently selected halo or–CN.
  • R4c is C 1-6 alkyl substituted with one, two, or three independently selected halo or–CN.
  • R4c is C1-6 alkyl substituted with one or more independently selected F, Cl, or–CN.
  • R4c is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )2, or -C(CH 3 )3, each of which is substituted with one, two, or three independently selected halo or–CN.
  • R4c is C1-6 alkyl substituted with one, two, or three independently selected F, Cl, or–CN.
  • R4c is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one or more independently selected F, Cl, or–CN.
  • R4c is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )2, or -C(CH 3 )3, each of which is substituted with one, two, or three independently selected F, Cl, or–CN.
  • R4c is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )2, or -C(CH 3 )3, each of which is substituted with one or more F or–CN.
  • R4c is C1-6 alkyl substituted with one, two, or three independently selected F or–CN.
  • R4c is -CH 2 CH 3 substituted with one, two, or three F.
  • R4c is -CH 2 -CN.
  • R4c is -CH 2 CF3.
  • the compound of the invention is according to Formula I, wherein Z is monocyclic or spirocyclic N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S.
  • Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 1-thia-6-azaspiro[3.3]heptanyl, or 2-thia-6-azaspiro[3.3]heptanyl.
  • Z is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptanyl, or 2-thia-6-azaspiro[3.3]heptanyl.
  • the compound of the invention is according to Formula I, wherein Z is monocyclic or spirocyclic N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R5 groups.
  • Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6- azaspiro[3.3]heptanyl, or 2-thia-6-azaspiro[3.3]heptanyl, each of which is substituted with one, two or three independently selected R5 groups.
  • Z is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, thiomorpholinyl, or 2-thia-6-azaspiro[3.3]heptanyl, each of which is substituted with one, two or three independently selected R5 groups.
  • R5 is oxo, F, -CN, -OH, phenyl, cyclopropyl, or -CoCH.
  • the compound of the invention is according to Formula I, wherein Z is N- linked monocyclic or spirocyclic 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R5 groups, and R5 is -NR15aR15b, and each R15a and R15b is as previously described.
  • R15a and R15b are both H.
  • R15a and R15b are both C 1-4 alkyl.
  • R15a and R15b are -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • the compound of the invention is according to Formula I, wherein Z is N- linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R5 groups, and R5 is C 1-4 alkoxy.
  • R5 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 )2.
  • R5 is -O-CH 3 .
  • the compound of the invention is according to Formula I, wherein Z is N- linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R5 groups, and R5 is C 1-4 alkoxy substituted with one or more halo or phenyl.
  • R5 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 )2, each of which is substituted with one or more halo or phenyl.
  • R5 is C 1-4 alkoxy substituted with one, two, or three halo or phenyl. In yet another particular embodiment, R5 is C 1-4 alkoxy substituted with one or more F, Cl or phenyl. In a more particular embodiment, R5 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 )2, each of which is substituted with one or more F, Cl, or phenyl. In another more particular embodiment, R5 is C 1-4 alkoxy substituted with one, two, or three F, Cl, or phenyl. In yet another more particular embodiment, R5 is -O-CH 3 substituted with one, two, or three halo or phenyl. In a most particular embodiment, R5 is -O-CH 3 substituted with one, two, or three F. In another most particular embodiment, R5 is -O-CH 3 substituted with one phenyl.
  • the compound of the invention is according to Formula I, wherein Z is N- linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R5 groups, and R5 is C 1-4 alkyl.
  • R5 is -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R5 is -CH 3 .
  • the compound of the invention is according to Formula I, wherein Z is N- linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R5 groups, and R5 is C 1-4 alkyl substituted with one or more halo, -OH, or C 1-4 alkoxy.
  • R5 is -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 substituted with one or more halo, -OH, or C 1-4 alkoxy.
  • R5 is C 1-4 alkyl substituted with one, two, or three halo, -OH, or C 1-4 alkoxy.
  • R5 is C 1-4 alkyl substituted with one or more F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R5 is -CH 3 substituted with one, two, or three halo, -OH, or C 1-4 alkoxy.
  • R5 is C 1-4 alkyl substituted with one, two, or three F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R5 is -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one, two, or three F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R5 is -CH 3 substituted with one, two, or three F, or -OH.
  • the compound of the invention is according to Formula I, wherein Z is N- linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R5 groups, and R5 is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R5 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • the compound of the invention is according to any one of Formulae I-IIh, wherein Y is N.
  • the compound of the invention is according to any one of Formulae I-IIh, wherein Y is CR2b and R2b is halo or–OH.
  • R2b is F, Cl, or–OH.
  • R2b is F.
  • the compound of the invention is according to any one of Formulae I-IIh, wherein Y is CR2b and R2b is C 1-4 alkyl.
  • R2b is -CH 3 ,–CH 2 CH 3 , or–CH(CH 3 )2. In a more particular embodiment, R2b is–CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIh, wherein Y is CR2b and R2b is C 1-4 alkoxy.
  • R2b is–O-CH 3 ,–O-CH 2 CH 3 , or -O-CH(CH 3 )2.
  • R2b is–O-CH 3 or–O-CH 2 CH 3 .
  • R2b is–O-CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIh, wherein Y is CR2b and R2b is C 1-4 alkoxy substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R2b is–O-CH 3 ,–O-CH 2 CH 3 , or–O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R2b is C 1-4 alkoxy substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R2b is C 1-4 alkoxy substituted with one or more independently selected F, Cl, Br, -OH, -O-CH 3 ,–O-CH 2 CH 3 , or–O-CH(CH 3 ) 2 .
  • R2b is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R2b is C 1-4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, -OH, -O-CH 3 ,–O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R2b is -O-CH 3 , substituted with one, two, or three independently selected halo.
  • R2b is -O-CH 2 CH 3 , substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R2b is -O-CHF 2 , -O-CH 2 CH 2 -OH, or -O-CH 2 CH 2 -O-CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIh, wherein Y is CR2b, R2b is–NR12aR12b, and R12a and R12b are independently H or C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • R12a and R12b are both H.
  • one of R12a and R12b is H, and the other is C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • R12a and R12b are both C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • one of R12a and R12b is H, and the other is -CH 3 , -CH 2 CH 3 , or–CH(CH 3 )2.
  • one of R12a and R12b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2, each of which is substituted with one– OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 )2.
  • R2b is -NH-CH 3 , -NH-CH(CH 3 )2, or -NH-CH 2 CH 2 -OH.
  • the compound of the invention is according to Formula I, wherein Z is -NR4aR4b, and R4a and R4b are as previously described.
  • R4a is H.
  • R4a is C 1-4 alkyl.
  • R4a is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2.
  • R4a is -CH 3 .
  • the compound of the invention is according to Formula IIIa, IIIb, IIIc, or IIId:
  • R1a, R1b, R1c, and R4b are as described above.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is halo, -OH, -CN, or C 3-7 cycloalkyl.
  • R1b is F, Cl, -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R1b is F, -OH, -CN, cyclopropyl, or cyclobutyl.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is C 1-4 alkyl.
  • R1b is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is C 1-4 alkyl substituted with one or more independently selected–OH,–CN, or C 2-4 alkenyl.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R1b is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, 2-azaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6- azaspiro[3.3]heptanyl, or 2-thia-6-azaspiro[3.3]heptanyl.
  • R1b is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, or 2-oxa-6- azaspiro[3.3]heptanyl.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R9 groups.
  • R1b is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, 2-azaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6- azaspiro[3.3]heptanyl, or 2-thia-6-azaspiro[3.3]heptanyl, each of which is substituted with one, two, or three independently selected R9 groups.
  • R1b is azetidinyl, oxetanyl,
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R9 groups, and R9 is halo or -OH.
  • R9 is F, Cl, or –OH.
  • R9 is F or–OH.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R9 groups, and R9 is C 1-4 alkyl.
  • R9 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2.
  • R9 is -CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R9 groups, and R9 is C 1-4 alkyl substituted with one or more–OH.
  • R9 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one, two, or three -OH.
  • R9 is–CH 2 -OH.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b is -NR10aR10b, and each R10a and R10b are as previously described.
  • R10a and R10b are both H.
  • one of R10a and R10b is H, and the other is C 1-4 alkyl optionally substituted with one or more -OH.
  • R10a and R10b are both C 1-4 alkyl optionally substituted with one or more -OH.
  • one of R10a and R10b is H, and the other is -CH 3 , -CH 2 CH 3 , or–CH(CH 3 ) 2 .
  • one of R10a and R10b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one or more -OH.
  • R10a and R10b are both -CH 3 , -CH 2 CH 3 , or– CH(CH 3 ) 2 , each of which is optionally substituted with one or more -OH.
  • R1b is -NH-CH(CH 3 ) 2 , -NH-CH 2 CH 2 -OH, -N(CH 2 CH 3 ) 2 or–N(CH 3 )-CH 2 CH 2 -OH.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is halo, -OH, -CN, or C 3-7 cycloalkyl.
  • R1c is F, Cl, -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R1c is F, -OH, -CN, cyclopropyl, or cyclobutyl.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is C 1-4 alkyl.
  • R1c is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is C 1-4 alkyl substituted with one or more independently selected–OH,–CN, or C2-4 alkenyl.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R1c is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, 2-azaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6- azaspiro[3.3]heptanyl, or 2-thia-6-azaspiro[3.3]heptanyl.
  • R1c is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, or 2-oxa-6- azaspiro[3.3]heptanyl.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R9 groups.
  • R1c is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, 2-azaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6- azaspiro[3.3]heptanyl, or 2-thia-6-azaspiro[3.3]heptanyl, each of which is substituted with one, two, or three independently selected R9 groups.
  • R1c is azetidinyl, oxetanyl,
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R9 groups, and R9 is halo or -OH.
  • R9 is F, Cl, or –OH.
  • R9 is F or–OH.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R9 groups, and R9 is C 1-4 alkyl.
  • R9 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R9 is -CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R9 groups, and R9 is C 1-4 alkyl substituted with one or more–OH.
  • R9 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2, each of which is substituted with one, two, or three -OH.
  • R9 is–CH 2 -OH.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1c is -NR10aR10b, and each R10a and R10b is independently H or C 1-4 alkyl optionally substituted with one or more -OH.
  • R10a and R10b are both H.
  • one of R10a and R10b is H, and the other is C 1-4 alkyl optionally substituted with one or more -OH.
  • R10a and R10b are both C 1-4 alkyl optionally substituted with one or more -OH.
  • one of R10a and R10b is H, and the other is -CH 3 , -CH 2 CH 3 , or–CH(CH 3 )2.
  • one of R10a and R10b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2, each of which is substituted with one or more -OH.
  • R10a and R10b are both -CH 3 , -CH 2 CH 3 , or–CH(CH 3 )2, each of which is optionally substituted with one or more -OH.
  • R1c is -NH-CH(CH 3 )2, -NH-CH 2 CH 2 -OH, -N(CH 2 CH 3 )2 or–N(CH 3 )-CH 2 CH 2 -OH.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b and R1c together with the atom onto which they are attached form a C3-6 cycloalkyl.
  • R1b and R1c together with the atom onto which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl.
  • R1b and R1c together with the atom onto which they are attached form a cyclobutyl.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b and R1c together with the atom onto which they are attached form a 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R1b and R1c together with the atom onto which they are attached form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • R1b and R1c together with the atom onto which they are attached form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b and R1c together with the atom onto which they are attached form a 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R11 groups.
  • R1b and R1c together with the atom onto which they are attached form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two or three independently selected R11 groups.
  • R1b and R1c together with the atom onto which they are attached form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl, each of which is substituted with one, two or three independently selected R11 groups.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b and R1c together with the atom onto which they are attached form a 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R11 groups, and R11 is C 1-4 alkyl.
  • R11 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2.
  • R11 is -CH 3 or -CH(CH 3 )2.
  • the compound of the invention is according to any one of Formulae I-IIId, wherein R1b and R1c together with the atom onto which they are attached form a 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R11 groups, and R11 is C 1-4 alkyl substituted with one or more independently selected–CN or C 1-4 alkoxy.
  • R11 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2, each of which is substituted with one, two, or three independently selected -CN, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 )2.
  • R11 is–CH 2 -CN or -CH 2 CH 2 -O-CH 3 .
  • the compound of the invention is according to Formula IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVi, IVj, IVk, IVl, IVm, IVn, IVo, or IVp:
  • R1a and R4b are as described above.
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is C 1-6 alkyl.
  • R4b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH 3 , or -CH(CH 3 )CH(CH 3 ) 2 .
  • R4b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH(CH 3 ) 2 . In a most particular embodiment, R4b is -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH(CH 3 ) 2 .
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is C 1-6 alkyl substituted with one or more independently selected R13.
  • R4b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH 3 , or -CH(CH 3 )CH(CH 3 ) 2 , each of which is substituted with one or more independently selected R13.
  • R4b is C 1-6 alkyl substituted with one, two, or three independently selected R13.
  • R4b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , or -CH(CH 3 )CH(CH 3 ) 2 , each of which is substituted with one or more independently selected R13.
  • R4b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH 3 , or -CH(CH3)CH(CH 3 )2, each of which is substituted with one, two, or three independently selected R 13 .
  • R 4b is C 1-6 alkyl substituted with one R 13 .
  • R 4b is -CH 3 , -CH2CH3, -CH2CH2CH3, -CH(CH 3 )2, -C(CH 3 )3, or -CH(CH3)CH(CH3)2, each of which is substituted with one, two, or three independently selected R 13 .
  • R 4b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH 3 ) 2 , -CH 2 CH(CH 3 )2, -C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH3, or -CH(CH3)CH(CH3)2, each of which is substituted with one R 13 .
  • R 4b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , or -CH(CH3)CH(CH 3 ) 2 , each of which is substituted with one R 13 .
  • each R 13 is independently F,
  • the compound of the invention is according to Formula I wherein Z is -NR 4a R 4b and R 4a is as previously described, or any one of Formulae Illa-IVp, wherein R 4b is C 1-6 alkyl substituted with one or more independently selected R 13 , and R 13 is -NR 19a R 19b , and each R 19a and R 19b is as previously described.
  • R 19a and R 19b are both H.
  • one of R 19a and R 19b is H, and the other is C 1-4 alkyl.
  • R 19a and R 19b are both Ci- 4 alkyl.
  • one of R 19a and R 19b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R 19a and R 19b are -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • the compound of the invention is according to Formula I wherein Z is -NR 4a R 4b and R 4a is as previously described, or any one of Formulae Illa-IVp, wherein R 4b is C 1-6 alkyl substituted with one or more independently selected R 13 , and R 13 is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R 13 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • R 13 is oxetanyl, tetrahydrofuranyl, or morpholinyl.
  • the compound of the invention is according to Formula I wherein Z is -NR 4a R 4b and R 4a is as previously described, or any one of Formulae Illa-IVp, wherein R 4b is C 1-6 alkyl substituted with one or more independently selected R 13 , and R 13 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R 13 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.
  • R 13 is imidazolyl, pyrazolyl, or pyridinyl.
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is C1-6 alkyl substituted with one or more independently selected R13, and R13 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl.
  • R13 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected C 1-4 alkyl.
  • R13 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one C 1-4 alkyl.
  • R13 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 )2.
  • R13 is imidazolyl or pyrazolyl, each of which is substituted with one or more independently selected C 1-4 alkyl.
  • R13 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one C 1-4 alkyl.
  • R13 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R13 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R13 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more -CH 3 .
  • R13 is imidazolyl or pyrazolyl, each of which is substituted with one C 1-4 alkyl.
  • R13 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R13 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one -CH 3 . In a most particular embodiment, R13 is .
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is C 3-7 cycloalkyl.
  • R4b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R4b is cyclopropyl, cyclobutyl, cyclopentyl.
  • R4b is cyclopropyl.
  • the compound of the invention is according to Formula I wherein Z is -NR 4a R 4b and R 4a is as previously described, or any one of Formulae Illa-IVp, wherein R 4b is C3-7 cycloalkyl substituted with one or more independently selected R 14a .
  • R 4b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected R 14a .
  • R 4b is C3-7 cycloalkyl substituted with one, two, or three independently selected R 14a .
  • R 4b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected R 14a .
  • R 4b is C3-7 cycloalkyl substituted with one R 14a .
  • R 4b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one R 14a .
  • the compound of the invention is according to Formula I wherein Z is -NR 4a R 4b and R 4a is as previously described, or any one of Formulae Illa-IVp, wherein R 4b is C 3-7 cycloalkyl substituted with one or more independently selected R 14a , and R 14a is halo, -OH, or C 1-4 alkoxy.
  • R 14a is F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -0-CH(CH 3 ) 2 .
  • R 14a is F, -OH, or -O-CH 3 .
  • R 4b is or .
  • a most particular embodiment R 14a is F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -0-CH(CH 3 ) 2 .
  • the compound of the invention is according to Formula I wherein Z is -NR 4a R 4b and R 4a is as previously described, or any one of Formulae Illa-IVp, wherein R 4b is C 3-7 cycloalkyl substituted with one or more independently selected R 14a , and R 14a is C 1-4 alkyl.
  • R 14a is -CH3, -CH 2 CH3, or -CH(CH 3 ) 2 .
  • R 14a is -CH 2 CH3 or -CH(CH3) 2 .
  • the compound of the invention is according to Formula I wherein Z is -NR 4a R 4b and R 4a is as previously described, or any one of Formulae Illa-IVp, wherein R 4b is C 3-7 cycloalkyl substituted with one or more independently selected R 14a , and R 14a is C 1-4 alkyl substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R 14a is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo, -OH, or Ci- 4 alkoxy.
  • R 14a is C 1-4 alkyl substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R 14a is C H alkyl substituted with one or more F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -0-CH(CH 3 ) 2 .
  • R 14a is -CH 3 substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R 14a is C H alkyl substituted with one halo, -OH, or C 1-4 alkoxy.
  • R 14a is C 1-4 alkyl substituted with one or more independently selected F or -OH.
  • R 14a is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R 14a is C 1-4 alkyl substituted with one, two, or three independently selected F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -0-CH(CH 3 ) 2 .
  • R 14a is -CH 2 -O-CH 3 .
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is C 3-7 cycloalkyl substituted with one or more independently selected R14a, and R14a is–NR20aR20b, and each R20a and R20b is as previously described.
  • R20a and R20b are both H.
  • one of R20a and R20b is H, and the other is C 1-4 alkyl.
  • R20a and R20b are both C 1-4 alkyl.
  • one of R20a and R20b is H, and the other is -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 )2.
  • R20a and R20b are -CH 3 ,– CH 2 CH 3 , or -CH(CH 3 )2.
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R4b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • R4b is oxetanyl, thietanyl, or tetrahydrofuranyl.
  • R4b is oxetanyl or tetrahydrofuranyl.
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R14b.
  • R4b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl , each of which is substituted with one or more independently selected R14b.
  • R4b is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected R14b.
  • R4b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R14b.
  • R4b is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one R14b.
  • R4b is thietanyl substituted with two R14b.
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R14b, and R14b is halo, oxo, -OH, or C 1-4 alkoxy.
  • R14b is F, Cl, oxo, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 )2.
  • R14b is F, oxo, -OH, or -O-CH 3 . In a most particular embodiment, R14b is oxo.
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R14b, and R14b is C 1-4 alkyl.
  • R14b is -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 )2. In a more particular embodiment, R14b is -CH 3 .
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R14b, and R14b is C 1-4 alkyl substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R14b is -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 )2, each of which is substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R14b is C 1-4 alkyl substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R14b is C 1-4 alkyl substituted with one or more F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R14b is -CH 3 substituted with one or more independently selected halo, -OH, or C 1-4 alkoxy.
  • R14b is C 1-4 alkyl substituted with one halo, -OH, or C 1-4 alkoxy.
  • R14b is C 1-4 alkyl substituted with one or more independently selected F or -OH.
  • R14b is -CH 3 , –CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo, -OH, or C 1-4 alkoxy.
  • R14b is C 1-4 alkyl substituted with one, two, or three independently selected F, Cl, -OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R14b is–CH 2 F, -CHF 2 , -CF 3 , or -CH 2 -OH.
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R14b, R14b is– NR20aR20b, and each R20a and R20b is as previously described.
  • R20a and R20b are both H.
  • one of R20a and R20b is H, and the other is C 1-4 alkyl.
  • R20a and R20b are both C 1-4 alkyl.
  • one of R20a and R20b is H, and the other is -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R20a and R20b are -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 )2.
  • R20a and R20b are -CH 3 .
  • the compound of the invention is according to any one of Formulae I and IIIa- IVp, wherein Z is–NR4aR4b, R4a is as previously described, and R4b is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R4b is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.
  • R4b is imidazolyl, pyrazolyl, isoxazolyl, or pyrimidinyl.
  • R4b is isoxazolyl.
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl.
  • R4b is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected C 1-4 alkyl.
  • R4b is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one C 1-4 alkyl.
  • R4b is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 )2.
  • R4b is imidazolyl, pyrazolyl, or pyrimidinyl, each of which is substituted with one or more independently selected C 1-4 alkyl.
  • R4b is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one -CH 3 .
  • R4b is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one C 1-4 alkyl.
  • R4b is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R4b is imidazolyl, pyrazolyl, or pyrimidinyl, each of which is substituted with one C 1-4 alkyl.
  • R4b is R4b is imidazolyl, pyrazolyl, or pyrimidinyl, each of which is substituted with one or more -CH 3 ,–CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R4b is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one or more -CH 3 .
  • R4b is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2.
  • R4b is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one -CH 3 .
  • R4b is imidazolyl, pyrazolyl, or pyrimidinyl, each of which is substituted with one–CH 3 .
  • the compound of the invention is according to Formula I wherein Z is -NR4aR4b and R4a is as previously described, or any one of Formulae IIIa-IVp, wherein R4b is cyclopropyl or 2- fluorocyclopropyl.
  • Z is–NR4aR4b, R4a is H, and R4b is cyclopropyl or (1R,2S)- 2-fluorocyclopropyl.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is H.
  • R1a is -CN.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C1-6 alkyl.
  • R1a is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )2, -CH 2 CH(CH 3 )2, -C(CH 3 )3, -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 )C H(CH 3 )2, -CH 2 CH(CH 3 )CH 2 CH 3 , or –CH 2 CH 2 CH(CH 3 )2.
  • R1a is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C 1-6 alkyl substituted with one or more independently selected R6.
  • R1a is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , or–CH 2 CH 2 CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected R6.
  • R1a is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , or -CH 2 CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected R6.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C 1-6 alkyl substituted with one or more independently selected R6, and R6 is halo.
  • R6 is F or Cl.
  • R1a is–CHF 2 or–CF 3 .
  • R1a is–CF 3 .
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C 1-6 alkyl substituted with one or more independently selected R6, R6 is -O-R16, and R16 is as previously described.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C1-6 alkyl substituted with one or more independently selected R6, R6 is -O-R16, and R16 is C 1-4 alkyl.
  • R16 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2. In a more particular embodiment, R16 is -CH 3 .
  • R16 is -CH 3 substituted with one–C(CH 3 )
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C1-6 alkyl substituted with one or more independently selected R6, R6 is -O-R16, and R16 is 4- 6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R16 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. In a more particular embodiment, R16 is oxetanyl.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C1-6 alkyl substituted with one or more independently selected R6, R6 is -NR17aR17b, and R17a and R17b are as previously described.
  • R17a and R17b are both H.
  • one of R17a and R17b is H, and the other is C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • R17a and R17b are both C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • one of R17a and R17b is H, and the other is -CH 3 , -CH 2 CH 3 , or–CH(CH 3 ) 2 .
  • one of R17a and R17b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one -OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R6 is -NH 2 , -NH-CH(CH 3 ) 2 , or–N(CH 3 )-CH 2 CH 2 -OH.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C 1-6 alkyl substituted with one or more independently selected R6, and R6 is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R6 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.
  • R6 is imidazolyl, pyrazolyl, or 1,2,4-triazolyl.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C 1-6 alkyl substituted with one or more independently selected R6, and R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • R6 is pyrrolidinyl, piperidinyl, or morpholinyl.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C1-6 alkyl substituted with one or more independently selected R6, and R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected halo.
  • R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three F or Cl.
  • R6 is azetidinyl substituted with one, two,
  • R6 is .
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C 1-4 alkoxy.
  • R1a is aboutO-CH 3 ,–O-CH 2 CH 3 , or–O-CH(CH 3 )2.
  • R1a is–O-CH 3 or–O-CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is C 1-4 alkoxy substituted with one or more–OH or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R1a is–O-CH 3 ,–O-CH 2 CH 3 , or–O-CH(CH 3 )2, each of which is substituted with one–OH, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • R1a is -O-CH 2 CH 3 substituted with one–OH or morpholinyl.
  • R7 is–OH, C 1-4 alkyl, or C 1-4 alkoxy.
  • R7 is -OH, -CH 3 , -CH 2 CH 3 , -CH(CH 3 )2, -O-CH 3 ,–O-CH 2 CH 3 , or–O-CH(CH 3 )2.
  • R7 is -OH, -CH 3 , or -O-CH 3 .
  • R18a and R18b are both H.
  • one of R18a and R18b is H, and the other is C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • R18a and R18b are both C 1-4 alkyl optionally substituted with one -OH or C 1-4 alkoxy.
  • one of R18a and R18b is H, and the other is -CH 3 , -CH 2 CH 3 , or–CH(CH 3 ) 2 .
  • one of R17a and R17b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one -OH, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R7 is -NH2, -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 2 CH 3 )2, –NH-CH 2 CH 2 -OH, or -NH-CH 2 CH 2 -O-CH 3 .
  • R7 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • R7 is morpholinyl.
  • R7 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three–OH.
  • R7 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three–OH.
  • R7 is azetidinyl, oxetanyl, pyrrolidinyl, tetra
  • R7 is azetidinyl substituted with one–OH.
  • R7 is .
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is -NR8aR8b, and each R8a and R8b are as previously described.
  • R8a and R8b are both H.
  • one of R8a and R8b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one, two, or three F, Cl, -CN, or -OH.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R1a is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.
  • R1a is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, or tetrazolyl.
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl.
  • R1a is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 CH 3 , or -CH(CH 3 )2.
  • R1a is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, or tetrazolyl, each of which is substituted with one -CH 3 .
  • R1a is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, or tetrazolyl, each of which is substituted with one -CH 3 .
  • R1a is .
  • the compound of the invention is according to any one of Formulae I-IVp, wherein R1a is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R1a is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • R1a is oxetanyl, tetrahydropyranyl, or morpholinyl.
  • the compound of the invention is according to Formula I, wherein the compound is selected from:
  • the compound of the invention is according to Formula I, wherein the compound is selected from:
  • the compound of the invention is according to Formula I, wherein the compound is 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N- [(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide.
  • the compound of the invention is according to Formula I, wherein the compound is not 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N- [(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide.
  • the compound of the invention is according to Formula I, wherein the compound is 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2- (difluoromethoxy)-6-methoxy-benzamide.
  • the compound of the invention is according to Formula I, wherein the compound is not 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2- (difluoromethoxy)-6-methoxy-benzamide.
  • a compound of the invention is not an isotopic variant.
  • a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.
  • a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7- C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
  • a compound of the invention When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • a compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • a compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington’s Pharmaceutical Sciences. (Remington 1985)
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press. Formulation 2 - Capsules
  • a compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
  • Formulation 3 - Liquid A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No.10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press. Formulation 5 - Injection
  • a compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75oC and then a mixture of a compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • Formula I 50 g
  • methylparaben (0.25 g
  • propylparaben (0.15 g
  • propylene glycol (120 g) dissolved in water about 370 g
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of inflammatory diseases.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of inflammatory diseases.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with inflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a inflammatory diseases treatment agent.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of autoinflammatory diseases.
  • autoinflammatory diseases refers to Cryopyrin- Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still’s disease.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of autoinflammatory diseases.
  • autoinflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still’s disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoinflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • autoinflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still’s disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a autoinflammatory diseases treatment agent.
  • autoinflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still’s disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of autoimmune diseases.
  • autoimmune diseases refers to COPD, asthma , bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of autoimmune diseases.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoimmune diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • autoimmune diseases refers to COPD, asthma , bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is an autoimmune diseases treatment agent.
  • autoimmune diseases refers to COPD, asthma , bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of proliferative diseases.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of proliferative diseases.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a proliferative diseases treatment agent.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of fibrotic diseases.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • NASH nonalcoholic steatohepatitis
  • systemic sclerosis idiopathic pulmonary fibrosis
  • renal fibrosis nonalcoholic steatohepatitis
  • cutaneous fibrosis fibrotic diseases.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of fibrotic diseases.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • NASH nonalcoholic steatohepatitis
  • systemic sclerosis renal fibrosis
  • cutaneous fibrosis fibrotic diseases
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with fibrotic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a fibrotic diseases treatment agent.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of transplantation rejection.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to graft-versus-host disease.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of transplantation rejection.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to graft-versus-host disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with transplantation rejection, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.
  • the term refers to graft-versus-host disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a transplantation rejection treatment agent.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to graft-versus-host disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases involving impairment of cartilage turnover.
  • diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of diseases involving impairment of cartilage turnover.
  • diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases involving impairment of cartilage turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases involving impairment of cartilage turnover treatment agent.
  • diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis,
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of congenital cartilage malformation.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of congenital cartilage malformation.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with congenital cartilage malformation, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a congenital cartilage malformation treatment agent.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases involving impairment of bone turnover.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of diseases involving impairment of bone turnover.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases involving impairment of bone turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases involving impairment of bone turnover treatment agent.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases associated with hypersecretion of IL-6.
  • diseases associated with hypersecretion of IL-6 refers to Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and/or mesangial proliferative glomerulonephritis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of diseases associated with hypersecretion of IL-6.
  • diseases associated with hypersecretion of IL-6 refers to Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and/or mesangial proliferative glomerulonephritis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases associated with hypersecretion of IL-6, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • diseases associated with hypersecretion of IL-6 refers to Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and/or mesangial proliferative glomerulonephritis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases associated with hypersecretion of IL-6 treatment agent.
  • diseases associated with hypersecretion of IL-6 refers to Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and/or mesangial proliferative glomerulonephritis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23.
  • diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • the term refers to Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23.
  • diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • the term refers to Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • the term refers to Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23 treatment agent.
  • diseases associated with hypersecretion of TNFa, interferons, IL-12 and/or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • the term refers to Sjögren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn’s disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of respiratory diseases.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of respiratory diseases.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with respiratory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a respiratory diseases treatment agent.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of endocrine and/or metabolic diseases.
  • endocrine and/or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and/or type II diabetes.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of endocrine and/or metabolic diseases.
  • endocrine and/or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and/or type II diabetes.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with endocrine and/or metabolic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • endocrine and/or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and/or type II diabetes.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a endocrine and/or metabolic diseases treatment agent.
  • endocrine and/or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and/or type II diabetes.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of cardiovascular diseases.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue.
  • the term refers to atherosclerosis or giant cell arteritis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of cardiovascular diseases.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with cardiovascular diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a cardiovascular diseases treatment agent.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of dermatological diseases.
  • dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren- Larsson syndrome, or urticaria.
  • the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of dermatological diseases.
  • dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with dermatological diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a dermatological diseases treatment agent.
  • dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of abnormal angiogenesis associated diseases.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet- form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of abnormal angiogenesis associated diseases.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with abnormal angiogenesis associated diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a abnormal angiogenesis associated diseases treatment agent.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.
  • Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • one to four (1-4) regular doses daily especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens.
  • dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
  • each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • a compound of the invention When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • a compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration.
  • co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament.
  • said pharmaceutical composition additionally comprises a further active ingredient.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of a disease involving inflammation
  • agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.
  • immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).
  • NSAIDS non-steroidal anti-inflammatory drugs
  • DMARDS for example but without limitation methotrexate, leflunom
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders
  • therapeutic agents include but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g.
  • the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery.
  • the proliferative disorder is selected from cancer, myeloproliferative disease or leukemia.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of autoimmune diseases
  • agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g.
  • anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies Atgam® and Thymoglobuline®
  • cyclosporin tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-b), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of transplant rejection
  • agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Ra receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)).
  • calcineurin inhibitors e.g. cyclosporin or tacrolimus (FK506)
  • mTOR inhibitors e.g. sirol
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of asthma and/or rhinitis and/or COPD
  • particular agents include but are not limited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled), long-acting b2-agonists (e.g.
  • salmeterol, formoterol, bambuterol, and sustained-release oral albuterol combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. cetirizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).
  • bronchodilators e.g. fluticasone/salmeterol, budesonide/formote
  • a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g.
  • oxygen or heliox administration ebulized salbutamol or terbutaline
  • an anticholinergic e.g. ipratropium
  • systemic steroids oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone
  • intravenous salbutamol e.g. pred
  • epinephrine isoetharine, isoproterenol, metaproterenol
  • anticholinergics IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium
  • methylxanthines theophylline, aminophylline, bamiphylline
  • inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of inflammatory bowel disease (IBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
  • glucocorticoids e.g. prednisone, budesonide
  • immunomodulatory agents e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of SLE
  • particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), Disease-modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.
  • DMARDs Disease-modifying antirheumatic drugs
  • antimalarials e.g. plaquen
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of psoriasis
  • particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort®), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologics such as Amevive®, Enbrel®, Humira®
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of allergic reaction
  • therapeutic agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or anti- leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.
  • antihistamines e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine
  • glucocorticoids e.g. prednisone, betamethasone, beclomethasone, dexamethasone
  • epinephrine e
  • any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person.
  • the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential.
  • the agents may be administered in different formulations and at different times.
  • the compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • a compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • Biotage® ISOLUTE® phase separators (e.g., Cat# 120-1907-E) are used for aqueous phase separation.1H NMR spectra are recorded on a Bruker DPX 400 NMR spectrometer (400 MHz) or a Bruker Avance 300 NMR spectrometer (300 MHz). Chemical shifts (d) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (d 0.00) or the appropriate residual solvent peak, i.e. CHCl3 (d 7.27), as internal reference.
  • Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer.
  • the methods are using ACN/H2O gradients with either 0.1% formic acid in both mobile phases, 0.05% NH3 in both mobile phases, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia).
  • Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBRIDGE BEH C18 OBD 30 mm ID ⁇ 100/150 mm L columns and ACN/H 2 O gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in H 2 O, or 10 mM NH 4 HCO 3 in H 2 O (adjusted to pH 10 with ammonia).
  • Microwave heating is performed with a Biotage® Initiator.
  • Method K1 Amine functionalization by reductive amination
  • Method K2 Ketone functionalization by reductive amination
  • reaction mixture is stirred at 140 °C for 30 min to 6 h then cooled to RT and filtered on DicaliteTM, rinsed with EtOAc and concentrated in vacuo.
  • the residue is purified by flash chromatography on silica gel.
  • the reaction mixture is directly concentrated in vacuo and the residue is purified by flash chromatography on silica gel.
  • the reaction mixture is heated to 80 °C for 2 to 18 h then filtered on Clarcel® and concentrated in vacuo.
  • the residue is diluted with water and extracted with EtOAc.
  • the combined organic layers are dried over MgSO4, filtered or passed through a phase separator and concentrated.
  • the residue is purified by flash chromatography.
  • Alternative work-up The reaction mixture is diluted with EtOAc, stirred for 1 h, filtered over Clarcel® and quenched with a sat. NH4Cl solution.
  • the solution is stirred for 30 min before addition of a 2N NaOH solution and extraction with EtOAc.
  • the combined organic layers are washed with a 10% aq. Na2S2O3 solution, brine, dried over Na2SO4, filtered and concentrated.
  • the residue is purified by flash chromatography on silica gel.
  • degassed DMAC In a sealed vial under N2 atmosphere are introduced degassed DMAC, halogenated heteroaryl compound (1 eq.), the alkyl bromide (1.5 to 2 eq.), NiCl2.glyme (CAS# 29046-78-4; 0.05 to 0.1 eq.), Int 230 (0.05 to 0.1 eq.), sodium iodide (CAS# 7681-82-5; 0.25 eq.), zinc powder (CAS# 7440-66-6; 2 eq.) and TFA (CAS# 76-05-1; 0.1 eq.).
  • the resulting solution is heated to 60 °C for 1 to 18 h then filtered on Clarcel®, washed with EtOAc and concentrated in vacuo. The residue is purified by flash chromatography on silica gel.
  • reaction mixture is cooled at RT and filtered over DicaliteTM.
  • the filtrate is diluted with brine and water, extracted with EtOAc.
  • the combined organic layers are dried over MgSO4 or Na2SO4, filtered and concentrated to dryness.
  • the residue is purified by flash chromatography on silica gel.
  • the mixture is stirred at 130 °C for 3.5 h, then at 90 °C for 18 h.
  • the reaction mixture is cooled at RT and filtered over DicaliteTM.
  • the filtrate is diluted with brine and water, extracted with EtOAc.
  • the combined organic layers are dried over Na2SO4, filtered and concentrated to dryness.
  • the residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 98/2) to afford the desired intermediate.
  • a pressure reactor or an open round bottom flask equipped with a condenser is charged with heteroarylbromide or iodide derivative (1 eq.), boronic acid or boronic acid pinacol ester (1.2 to 1.5 eq.), a base (Cs 2 CO 3 , K 2 CO 3 , or KF, 1.3 to 3 eq.) and dioxane/water solvent mixture: 4/1 or 3/1 or DMF/water solvent mixture: 4/1.
  • the mixture is either heated to 100 °C, degassed with N 2 then Pd catalyst (Pd(PPh 3 ) 4 CAS# 14221-01-3; Pd(dppf)Cl 2 ⁇ DCM adduct CAS# 95464-05-4; or Xphos Pd G3 CAS# 1445085-55-1; 0.07 to 0.2 eq.) is added, or degassed with N 2 or Ar at RT before addition of the Pd catalyst.
  • the mixture is stirred at 90 to 100 °C for 5 min to 18 h.
  • the reaction mixture is concentrated in vacuo or not, and diluted in EtOAc or DCM and water or a sat. NaHCO 3 solution.
  • the resulting mixture is filtered over sand or DicaliteTM or not.
  • the mixture is then extracted with EtOAc or DCM.
  • the combined organic layers are optionally washed with brine, dried over anhydrous Na 2 SO 4 or MgSO 4 , filtered, or passed through a phase separator, and then concentrated in vacuo.
  • the residue is purified by flash chromatography on silica gel to afford the expected compound.

Abstract

La présente invention porte sur des composés de formule (I), dans laquelle R1a, R1b, R1c, R2a, W1, W2, X1, X2, X3, Y, et Z sont tels que définis dans la description. La présente invention concerne des composés, des procédés pour leur production, des compositions pharmaceutiques les comprenant et des méthodes de traitement les utilisant, pour la prophylaxie et/ou le traitement de maladies inflammatoires, de maladies auto-inflammatoires, de maladies auto-immunes, de maladies prolifératives, de maladies fibrotiques, d'un rejet de transplantation, de maladies impliquant une déficience du renouvellement du cartilage, de malformations congénitales du cartilage, de maladies impliquant une déficience du renouvellement osseux, de maladies associées à une hypersécrétion de l'IL-6, de maladies associées à une hypersécrétion du TNFα, d'interférons, d'IL-12 et/ou d'IL-23, de maladies respiratoires, des maladies endocrines et/ou métaboliques, de maladies cardiovasculaires, de maladies dermatologiques et/ou de maladies associées à une angiogenèse anormale par administration du composé selon l'invention.
PCT/EP2020/064368 2019-05-29 2020-05-25 Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies WO2020239658A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
EA202193281A EA202193281A1 (ru) 2019-05-29 2020-05-25 Новые соединения и их фармацевтические композиции для лечения заболеваний
SG11202112652RA SG11202112652RA (en) 2019-05-29 2020-05-25 Novel compounds and pharmaceutical compositions thereof for the treatment of diseases
JP2021570425A JP2022534578A (ja) 2019-05-29 2020-05-25 新規化合物及び疾患の治療のためのその医薬組成物
EP20728465.4A EP3976189A1 (fr) 2019-05-29 2020-05-25 Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies
CA3141683A CA3141683A1 (fr) 2019-05-29 2020-05-25 Nouveaux composes et compositions pharmaceutiques associees pour le traitement de maladies
CN202080039185.0A CN113924146A (zh) 2019-05-29 2020-05-25 用于治疗疾病的新化合物及其药物组合物
AU2020281650A AU2020281650A1 (en) 2019-05-29 2020-05-25 Novel compounds and pharmaceutical compositions thereof for the treatment of diseases
KR1020217042863A KR20220015450A (ko) 2019-05-29 2020-05-25 질병의 치료를 위한 신규 화합물 및 그의 약학 조성물
CR20210586A CR20210586A (es) 2019-05-29 2020-05-25 Nuevos compuestos y sus composiciones farmacéuticas para el tratamiento de enfermedades
BR112021023900A BR112021023900A2 (pt) 2019-05-29 2020-05-25 Compostos e composições farmacêuticas dos mesmos para o tratamento de doenças
MX2021013803A MX2021013803A (es) 2019-05-29 2020-05-25 Nuevos compuestos y sus composiciones farmaceuticas para el tratamiento de enfermedades.
PE2021001955A PE20220503A1 (es) 2019-05-29 2020-05-25 Nuevos compuestos y sus composiciones farmaceuticas para el tratamiento de enfermedades
US17/614,854 US20220340548A1 (en) 2019-05-29 2020-05-25 Novel compounds and pharmaceutical compositions thereof for the treatment of diseases
IL288375A IL288375A (en) 2019-05-29 2021-11-24 New compounds and their pharmaceutical preparations for the treatment of diseases
CONC2021/0017656A CO2021017656A2 (es) 2019-05-29 2021-12-22 Nuevos compuestos y sus composiciones farmaceuticas para el tratamiento de enfermedades

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1907616.5 2019-05-29
GBGB1907616.5A GB201907616D0 (en) 2019-05-29 2019-05-29 Novel compounds and pharmaceutical compositons thereof for the treatment of diseases

Publications (1)

Publication Number Publication Date
WO2020239658A1 true WO2020239658A1 (fr) 2020-12-03

Family

ID=67385363

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/064368 WO2020239658A1 (fr) 2019-05-29 2020-05-25 Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies

Country Status (21)

Country Link
US (1) US20220340548A1 (fr)
EP (1) EP3976189A1 (fr)
JP (1) JP2022534578A (fr)
KR (1) KR20220015450A (fr)
CN (1) CN113924146A (fr)
AR (1) AR119028A1 (fr)
AU (1) AU2020281650A1 (fr)
BR (1) BR112021023900A2 (fr)
CA (1) CA3141683A1 (fr)
CL (1) CL2021003133A1 (fr)
CO (1) CO2021017656A2 (fr)
CR (1) CR20210586A (fr)
EA (1) EA202193281A1 (fr)
GB (1) GB201907616D0 (fr)
IL (1) IL288375A (fr)
MA (1) MA56019A (fr)
MX (1) MX2021013803A (fr)
PE (1) PE20220503A1 (fr)
SG (1) SG11202112652RA (fr)
TW (1) TW202110839A (fr)
WO (1) WO2020239658A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023066204A1 (fr) * 2021-10-18 2023-04-27 上海美悦生物科技发展有限公司 Inhibiteur de sik, composition de celui-ci, son procédé de préparation et son utilisation
WO2023139085A1 (fr) * 2022-01-19 2023-07-27 F. Hoffmann-La Roche Ag Nouveaux dérives de benzimidazole pyridine
WO2024003209A1 (fr) * 2022-07-01 2024-01-04 F. Hoffmann-La Roche Ag Dérivés d'imidazo [4,5-c] pyridine en tant que modulateurs de sik pour le traitement de la polyarthrite rhumatoïde

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USD982434S1 (en) * 2021-08-31 2023-04-04 Level Up Dice LLC Dice storage container
CN115304605B (zh) * 2022-01-21 2023-10-03 陕西国际商贸学院 具有抗肿瘤活性的氧杂环丁烷衍生物及其制备方法和应用
CN116813608B (zh) * 2023-06-08 2024-03-22 英矽智能科技(上海)有限公司 噻唑类化合物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012068406A2 (fr) * 2010-11-18 2012-05-24 Ligand Pharmaceuticals Incorporated Utilisation de mimétiques d'un facteur de croissance hématopoïétique
WO2014093383A1 (fr) * 2012-12-14 2014-06-19 Arrien Pharmaceuticals Llc Dérivés substitués de 1h-pyrrolo[2,3-b]pyridine et 1h-pyrazolo[3,4-b]pyridine en tant qu'inhibiteurs de kinases 2 inductibles par un sel (sik2)
WO2019105886A1 (fr) * 2017-12-02 2019-06-06 Galapagos Nv Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2605946T3 (es) * 2012-03-14 2017-03-17 Bayer Intellectual Property Gmbh Imidazopiridazinas sustituidas
CN108358894B (zh) * 2018-04-26 2021-05-07 四川大学 一种抑制组蛋白乙酰转移酶的化合物及其制备方法与应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012068406A2 (fr) * 2010-11-18 2012-05-24 Ligand Pharmaceuticals Incorporated Utilisation de mimétiques d'un facteur de croissance hématopoïétique
WO2014093383A1 (fr) * 2012-12-14 2014-06-19 Arrien Pharmaceuticals Llc Dérivés substitués de 1h-pyrrolo[2,3-b]pyridine et 1h-pyrazolo[3,4-b]pyridine en tant qu'inhibiteurs de kinases 2 inductibles par un sel (sik2)
WO2019105886A1 (fr) * 2017-12-02 2019-06-06 Galapagos Nv Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1374014-30-8
REMINGTON'S PHARMACEUTICAL SCIENCES. (REMINGTON, 1985

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023066204A1 (fr) * 2021-10-18 2023-04-27 上海美悦生物科技发展有限公司 Inhibiteur de sik, composition de celui-ci, son procédé de préparation et son utilisation
WO2023139085A1 (fr) * 2022-01-19 2023-07-27 F. Hoffmann-La Roche Ag Nouveaux dérives de benzimidazole pyridine
WO2024003209A1 (fr) * 2022-07-01 2024-01-04 F. Hoffmann-La Roche Ag Dérivés d'imidazo [4,5-c] pyridine en tant que modulateurs de sik pour le traitement de la polyarthrite rhumatoïde

Also Published As

Publication number Publication date
MA56019A (fr) 2022-04-06
TW202110839A (zh) 2021-03-16
CR20210586A (es) 2022-01-24
AU2020281650A1 (en) 2022-02-03
US20220340548A1 (en) 2022-10-27
JP2022534578A (ja) 2022-08-02
GB201907616D0 (en) 2019-07-10
CL2021003133A1 (es) 2022-07-22
CO2021017656A2 (es) 2022-01-17
PE20220503A1 (es) 2022-04-07
CN113924146A (zh) 2022-01-11
MX2021013803A (es) 2021-12-14
SG11202112652RA (en) 2021-12-30
BR112021023900A2 (pt) 2022-01-18
IL288375A (en) 2022-01-01
KR20220015450A (ko) 2022-02-08
EP3976189A1 (fr) 2022-04-06
AR119028A1 (es) 2021-11-17
CA3141683A1 (fr) 2020-12-03
EA202193281A1 (ru) 2022-03-01

Similar Documents

Publication Publication Date Title
AU2018374456B2 (en) Novel compounds and pharmaceutical compositions thereof for the treatment of diseases
WO2020239658A1 (fr) Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies
EP3097083B1 (fr) Dérivés de benzimidazole et compositions pharmaceutiques de ceux-ci pour le traitement de troubles inflammatoires
CN112292129B (zh) 用于治疗疾病的新化合物及其药物组合物
WO2021032582A1 (fr) Dérivés de pyrazolo [4,3-c] pyridine et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires
EP3976178A1 (fr) Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies
RU2782375C2 (ru) Новые соединения и их фармацевтические композиции для лечения заболеваний
TW202411229A (zh) 用於治療發炎性病症之新穎化合物及其醫藥組合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20728465

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3141683

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021570425

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021023900

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 20217042863

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112021023900

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20211126

ENP Entry into the national phase

Ref document number: 2020728465

Country of ref document: EP

Effective date: 20220103

ENP Entry into the national phase

Ref document number: 2020281650

Country of ref document: AU

Date of ref document: 20200525

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 521430959

Country of ref document: SA